C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes
C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes
Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm’s body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism’s feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins’ mode of action.
Aldicarb, DFP, Neuromuscular junction, Organophosphate, Oxime, Paraoxon
50-62
Izquierdo, Patricia G.
bc166241-fb24-44c1-bf25-c25c384dedbe
O’connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Green, Christopher
3983c11c-522c-4bf2-bcf1-ba96e8fa6dd3
Holden-dye, Lindy
bfe6332d-d076-47c6-93c8-6987f7a886cd
Tattersall, John
9e52a76d-8729-4193-b41b-ca2339d271e5
January 2021
Izquierdo, Patricia G.
bc166241-fb24-44c1-bf25-c25c384dedbe
O’connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Green, Christopher
3983c11c-522c-4bf2-bcf1-ba96e8fa6dd3
Holden-dye, Lindy
bfe6332d-d076-47c6-93c8-6987f7a886cd
Tattersall, John
9e52a76d-8729-4193-b41b-ca2339d271e5
Izquierdo, Patricia G., O’connor, Vincent, Green, Christopher, Holden-dye, Lindy and Tattersall, John
(2021)
C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes.
NeuroToxicology, 82, .
(doi:10.1016/j.neuro.2020.11.001).
Abstract
Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm’s body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism’s feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins’ mode of action.
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Accepted/In Press date: 3 November 2020
e-pub ahead of print date: 8 November 2020
Published date: January 2021
Additional Information:
Funding Information:
This work was equally funded by the University of Southampton (United Kingdom) and the Defence Science and Technology Laboratory , Porton Down, Wiltshire (United Kingdom).
Funding Information:
We thank Aleksandra Pitera and Dr. Katrin Deinhardt for providing mouse brain homogenate. Additionally, C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ).
Publisher Copyright:
© 2020
Keywords:
Aldicarb, DFP, Neuromuscular junction, Organophosphate, Oxime, Paraoxon
Identifiers
Local EPrints ID: 445055
URI: http://eprints.soton.ac.uk/id/eprint/445055
ISSN: 0161-813X
PURE UUID: 7b707d1b-e466-443b-88b4-8f3336b9a57b
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Date deposited: 18 Nov 2020 17:32
Last modified: 06 Jun 2024 04:16
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Contributors
Author:
Patricia G. Izquierdo
Author:
Christopher Green
Author:
Lindy Holden-dye
Author:
John Tattersall
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